Therapeutic agent



Patented Mar. 5, 1940 I 2,192,828

UNITED STATES PATENT OFFlCE THERAPEUTIC AGENT Troy 0. Daniels, Burlingame, Califi, assignor to Research Corporation, New York, N. Y., a corporation of New York No Drawing. Application April 3, 1939, Serial No. 265,818

3 Claims. (Cl. 260-295) This invention relates to compounds adapted preparation of the nicotinyl derivatives. The to be administered in the treatment of bacterial best method which I have found for the preparainfections such as beta hemolytic streptococcus, tion of nicotinylsulfanilamide, i. e., the method pneumococcus, gonococcus, etc. which gives the most satisfactory yields is by Only a few of the several hundred compounds reacting nicotinyl chloride with dry sulfanilamide 5 heretofore studied have been found to be suitin the presence of anhydrous pyridine. This able and efiective in the treatment of such bacmethod in detail is as follows. Equal molecular terial infections. Among such compounds is pquantities of dry p-aminobenzenesulfonamide aminobenzenesulfonamide or sulfanilamide. It and nicotinyl chloride are placed in a dry reachas a relatively simple structure and is the basis tion flask with 1 cc. of dry pyridine for each or starting point of many of the other comgram of the sulfanilamide. The mixture is heatpounds or derivatives which have been prepared ed on a steam bath for 1 hour, cooled and 4-5 and tested. Recently 2-(p-aminobenzenesulfanvolumes of cold water added, allowed to stand amido) pyridine has been described nd i said 30 minutes and filtered. The residue is washed to be more effective in the treatment of pneu- With cold water and recrystallized from 50% mococcus infections than is sulfanilamide. The ethyl alcohol.

azo compounds derived from sulfanilamide are The yield obtained by reacting nicotinyl chlocommonly regarded as being less effective. I Benride on sulfanilamide in the presence of an zylaminobenzenesulfonamide has been used but drous benzene is not satisfactory. Likewise only probably also is less effective than sulfanilamide. a small yield is obtained by fusing a mixture of 0 I have found that the introduction of a niconicotinic acid and sulfanilamide at a temperature tinyl group into a compound of the type of sulof 180 C. for 2-3 hours with additions of small fanilamide improves its properties, in certain reamounts of dry toluene at intervals. Other methspects at least, for use in the treatment of such ods which have been tried are the reaction of infections. In the case of sulfanilamide for innicotinyl chloride with dry sulfanilamide in an- 25 stance the toxicity is reduced and the effectivehydrous acetone and the direct fusion of niconess of the resulting nicotinylsulfanilamide is tinic acid with dry sulfanilamide at 180 C. for greater for certain types of infections than sul- 4 to 5 hours. Since the invention is primarily fanilamide. concerned with the products I have not been par- Other examples of nicotinyl derivatives of the ticularly concerned with the method or methods 30 type referred to are the mono and dinicotinyl deof making themv excepting to the extent of deterrivatives of 4,4-diaminophenylsulfone, i. e., 4- mining that they can be made. Further renicotinylamino-4' aminophenylsulfone having search will no doubt result in better methods of t formula making the products.

The reactions involved in the production of o o OQO ELQ, nicotinylsulfanilamide areas follows E: g 0

H \N NH! (6 N (L;.

c0i L J and 4,4-dinicotinylaminophenylsulione having the formula 0 0 0 O Q N n i 0 o NH: -NH, 45

N N and 4-nicotinylamino-4'-N-methylene sodium Sull' nlla- Nicctm l i-mcotln laminobenzcne sulfinate of phenylsulfone having the formula i Chl r s su lionamide The product, purified by recrystallization from 50% ethyl alcohol, is a white crystalline solid N and when pure has a melting point of 257 C. Various methods may be employed for the (corrected). Its molecular weight is calculated 55 0 0 0 The nicotinyl chloride is prepared by reacting 50 NaO- @-lSl-C I-g-| nicotinic acid with thionyl chloride.

as being 277 and has been determined by Menges method as being 275.

The properties of sulfanilamide are considerably modified by the introduction of the nicotinyl group. Its solubility in water is decreased. The sodium salt of the nicotinylsulfanilamide undergoes hydrolysis readily in water thus showing the properties of a very weak acid whereas sulfanilamide similarly tested shows somewhat stronger acidic properties. The nicotinylsulfanilamide is considerably less toxic than sulfanilamide and is effective against streptococcus in doses only half as large. It is very slightly soluble in water but is somewhat soluble in organic solvents such as ethyl alcohol and propylene glycol. It is absorbed from mucous membranes including the gut and is excreted in the urine over a period of 24 hours either as such or in some other form in which the amino group is muzzled. Mice, rats and other small animals have been given dosages as high as 12 grams per kilogram, which is about as much as conveniently can be given by mouth, without fatality. In humans, doses of 0.5 gram, taken by mouth produce no evidence of local irritation or other objectionable efiect. It doses of 1 gram per day for five days, orally, it has been found to be about twice as efiective as sulfanilamide in protecting mice from death by streptococcus infections. In chronic pneumococcus infections in mice it seems more efiective in preventing death than sulfanilamide or sulfapyridine. Whereas central nervous system depression is observed in the use of sulfanilamide no such effect, even with maximum doses, is observed with the nicotinyl derivative.

A possible explanation of the superior properties of nicotinylsulfanilamide may be that the nicotinyl group acts as a carrier for the sulfanilamide into an infecting organism, thus improving its effectiveness. Moreover aromatic amines in general are capable of forming methemoglobin and it is therefore not surprising that sulfanilamide in large doses frequently cause methemoglobinemia. The blocking of the basic amino group of the sulfanilamide with the nicotinyl group may serve to minimize this tendency and at the same time result in a product of lower toxicity. Furthermore one of the toxic manifestations of sulfanilamide is a general dermatitis and since nicotinic acid. is Very effective in the correction of dermatitis associated with pellagra it is possible that it has a similar action in combination with sulfanilamide and thus renders the product free of this action.

So far as I am aware nicotinylsulfanilamide is the first instance of the successful internal use of nicotinic acid or any derivative of it as a bactericidal or bacteriostatic agent.

An objection to the nicotinylsulfanilamide of course is its low solubility which renders it unfit for parenteral administration and also less desirable in the case of serious emergencies requiring quick action, than the more soluble agents such as sulfanilamide.

I claim:

1. 4-nicotinylaminobenzenesulfonamide having the formula H t N-C 2. A bactericidal or bacteriostatic composition comprising as the active bactericidal or bacteriostatic agent 4-nicotinylaminobenzenesulfonamide.

3. The process of producing p-nicotinylaminobenzenesulfonamide, which consists in reacting p-amino-benzenesulfonamide with a nicotinyl chloride.

TROY C. DANIELS. 

